Structure and dynamics of the E. coli chemotaxis core signaling complex by cryo-electron tomography and molecular simulations

To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Despite decades of study, important questions surrounding the molecular mechanisms of sensory signal transduction remain unresolved, owing especially to the lack of a high-resolution CSU structure. Here, we use cryo-electron tomography and sub-tomogram averaging to determine a structure of the Escherichia coli CSU at sub-nanometer resolution. Based on our experimental data, we use molecular simulations to construct an atomistic model of the CSU, enabling a detailed characterization of CheA conformational dynamics in its native structural context. We identify multiple, distinct conformations of the critical P4 domain as well as asymmetries in the localization of the P3 bundle, offering several novel insights into the CheA signaling mechanism

The accuracy of intramedullary femoral alignment in total knee replacement in the prescence of ipsilateral hip replacement

Objectives: During total knee replacement (TKR) surgery, the most commonly used method for aligning the distal femur appropriately is via an intramedullary (IM) distal femoral alignment rod. The alignment of the rod itself is reliant on the isthmus which is used to most accurately place the rod in the correct anatomical axis. In the instance of something preventing the rod from entering the isthmus correctly, such as a hip replacement, then the degree of accuracy could be assumed to be even less. Mechanical-anatomical malalignment has been shown to decrease the implant (TKR) survival and so methods of increasing accuracy of alignment relative to the mechanical axis have been developed. At present the most accurate method intraoperatively is computer navigation and several studies have demonstrated improved alignment. An increasing number of patients year on year are having both knee and hip replacements and as the population ages the likelihood of having both a knee and hip replacement will also increase. We propose that the presence of a hip replacement within the isthmus of the femur may further decrease the accuracy of the IM alignment of the femur leading to incorrect implant positioning. Methods: The study was conducted on 10 cadaveric specimens (20 femurs). Computational navigation instrumentation was attached in turn to each femur and the ideal alignment data recorded in a standard fashion by a single operator (principal investigator). A standard entry port was then be made in the femur for the introduction of the IM rod. An IM rod was then inserted with the distal femoral cutting block in the accepted position recorded blindly on the computer navigation (both in terms of varus/valgus alignment to the mechanical axis and the degree of flexion). The process was then repeated at 3 levels to represent primary and revision hip lengths from the greater trochanter (replicating the changes that would occur in the presence of a hip replacement) The process was recorded three times at each level. Results: The resection angles between the cutting surface and the mechanical axis were measured and collected by means of computer navigation system. The results show that the IM alignment had mean Valgus of 0 degrees +/- 0.8 but with a hip replacement in situ this increased to 0.46 degrees +/- 1.49 (range 2.5 varus to 4.5 valgus), with a revision stem 0.825 +/- 1.68 (range 2.5 varus to 4.5 valgus)and long stemmed revision 1.325 +/- 2.09 (range 5 varus to 6.5 valgus). In terms of Flexion IM alignment had a mean flexion of 0.92 +/- 1.7 (range 3 extension to 4 flexion) but with a hip replacement in situ this increased to 1.88 degrees +/- 2.03 (range 2.5 extension to 8.5 flexion), with a revision stem 2.35 +/- 2.2 (range 2.5 extension to 8 flexion) and long stemmed revision 2.75 +/- 2.16(range 3.5 extension to 7 flexion). Conclusion: This Study concludes that the prescence of a hip replacement, in particular long stemmed prosthesis, further reduces the accuracy of IM alignment in the Femur for Total Knee Replacement. Consideration of an alternative method, such as navigation, should be considered insuch situations

Center, periphery: practice

info:eu-repo/semantics/publishedVersio

NEMBASE4: the nematode transcriptome resource

AbstractNematode parasites are of major importance in human health and agriculture, and free-living species deliver essential ecosystem services. The genomics revolution has resulted in the production of many datasets of expressed sequence tags (ESTs) from a phylogenetically wide range of nematode species, but these are not easily compared. NEMBASE4 presents a single portal into extensively functionally annotated, EST-derived transcriptomes from over 60 species of nematodes, including plant and animal parasites and free-living taxa. Using the PartiGene suite of tools, we have assembled the publicly available ESTs for each species into a high-quality set of putative transcripts. These transcripts have been translated to produce a protein sequence resource and each is annotated with functional information derived from comparison with well-studied nematode species such as Caenorhabditis elegans and other non-nematode resources. By cross-comparing the sequences within NEMBASE4, we have also generated a protein family assignment for each translation. The data are presented in an openly accessible, interactive database. To demonstrate the utility of NEMBASE4, we have used the database to examine the uniqueness of the transcriptomes of major clades of parasitic nematodes, identifying lineage-restricted genes that may underpin particular parasitic phenotypes, possible viral pathogens of nematodes, and nematode-unique protein families that may be developed as drug targets

KiDS-1000 Cosmology:Multi-probe weak gravitational lensing and spectroscopic galaxy clustering constraints

We present a joint cosmological analysis of weak gravitational lensing observations from the Kilo-Degree Survey (KiDS-1000), with redshift-space galaxy clustering observations from the Baryon Oscillation Spectroscopic Survey (BOSS), and galaxy-galaxy lensing observations from the overlap between KiDS-1000, BOSS and the spectroscopic 2-degree Field Lensing Survey (2dFLenS). This combination of large-scale structure probes breaks the degeneracies between cosmological parameters for individual observables, resulting in a constraint on the structure growth parameter $S_8=\sigma_8 \sqrt{\Omega_{\rm m}/0.3} = 0.766^{+0.020}_{-0.014}$, that has the same overall precision as that reported by the full-sky cosmic microwave background observations from Planck. The recovered $S_8$ amplitude is low, however, by $8.3 \pm 2.6$ % relative to Planck. This result builds from a series of KiDS-1000 analyses where we validate our methodology with variable depth mock galaxy surveys, our lensing calibration with image simulations and null-tests, and our optical-to-near-infrared redshift calibration with multi-band mock catalogues and a spectroscopic-photometric clustering analysis. The systematic uncertainties identified by these analyses are folded through as nuisance parameters in our cosmological analysis. Inspecting the offset between the marginalised posterior distributions, we find that the $S_8$-difference with Planck is driven by a tension in the matter fluctuation amplitude parameter, $\sigma_8$. We quantify the level of agreement between the CMB and our large-scale structure constraints using a series of different metrics, finding differences with a significance ranging between $\sim\! 3\,\sigma$, when considering the offset in $S_{8}$, and $\sim\! 2\,\sigma$, when considering the full multi-dimensional parameter space.Comment: 25 pages, 11 figures, 5 tables, A&A accepted, including a new appendix on Intrinsic Alignments. The KiDS-1000 data products are available for download at http://kids.strw.leidenuniv.nl/DR4/lensing.php. This data release includes open source software, the shear-photo-z catalogue, the cosmic shear and 3x2pt data vectors and covariances, and posteriors in the form of Multinest chain

Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data

<p>Abstract</p> <p>Background</p> <p>We introduce Glaucoma Discovery Platform (GDP), an online environment for facile visualization and interrogation of complex transcription profiling datasets for glaucoma. We also report the availability of Datgan, the suite of scripts that was developed to construct GDP. This reusable software system complements existing repositories such as NCBI GEO or EBI ArrayExpress as it allows the construction of searchable databases to maximize understanding of user-selected transcription profiling datasets.</p> <p>Description</p> <p>Datgan scripts were used to construct both the underlying data tables and the web interface that form GDP. GDP is populated using data from a mouse model of glaucoma. The data was generated using the DBA/2J strain, a widely used mouse model of glaucoma. The DBA/2J-<it>Gpnmb⁺</it>strain provided a genetically matched control strain that does not develop glaucoma. We separately assessed both the retina and the optic nerve head, important tissues in glaucoma. We used hierarchical clustering to identify early molecular stages of glaucoma that could not be identified using morphological assessment of disease. GDP has two components. First, an interactive search and retrieve component provides the ability to assess gene(s) of interest in all identified stages of disease in both the retina and optic nerve head. The output is returned in graphical and tabular format with statistically significant differences highlighted for easy visual analysis. Second, a bulk download component allows lists of differentially expressed genes to be retrieved as a series of files compatible with Excel. To facilitate access to additional information available for genes of interest, GDP is linked to selected external resources including Mouse Genome Informatics and Online Medelian Inheritance in Man (OMIM).</p> <p>Conclusion</p> <p>Datgan-constructed databases allow user-friendly access to datasets that involve temporally ordered stages of disease or developmental stages. Datgan and GDP are available from <url>http://glaucomadb.jax.org/glaucoma</url>.</p

Local Admixture of Amplified and Diversified Secreted Pathogenesis Determinants Shapes Mosaic \u3cem\u3eToxoplasma gondii\u3c/em\u3e Genomes

Toxoplasma gondii is among the most prevalent parasites worldwide, infecting many wild and domestic animals and causing zoonotic infections in humans. T. gondii differs substantially in its broad distribution from closely related parasites that typically have narrow, specialized host ranges. To elucidate the genetic basis for these differences, we compared the genomes of 62 globally distributed T. gondii isolates to several closely related coccidian parasites. Our findings reveal that tandem amplification and diversification of secretory pathogenesis determinants is the primary feature that distinguishes the closely related genomes of these biologically diverse parasites. We further show that the unusual population structure of T. gondii is characterized by clade-specific inheritance of large conserved haploblocks that are significantly enriched in tandemly clustered secretory pathogenesis determinants. The shared inheritance of these conserved haploblocks, which show a different ancestry than the genome as a whole, may thus influence transmission, host range and pathogenicity

Different molecular patterns in glioblastoma multiforme subtypes upon recurrence

One of the hallmarks of glioblastoma is its inherent tendency to recur. At this point patients with relapsed GBM show a survival time of only few months. The molecular basis of the recurrence process in GBM is still poorly understood. The aim of the present study was to investigate the genetic profile of relapsed GBM compared to their respective primary tumors. We have included 20 paired GBMs. In all tumor samples, we have analyzed p53 and PTEN status by sequencing analysis, EGFR amplification by semiquantitative PCR and a wide-genome fingerprinting was performed by microsatellite analysis. Among primary GBM, we observed twelve type 2 GBM, four type 1 GBM and four further GBM showing neither p53 mutations nor EGFR amplification (non-type 1–non-type 2 GBM). Upon recurrence, we have detected two molecular patterns of tumor progression: GBM initially showing either type 1 or type 2 profiles conserved them at the time of relapse. In contrast, non-type 1–non-type 2 GBM acquired the typical pattern of type 2 GBM and harbor EGFR amplification without p53 mutation. New PTEN mutations upon relapse were only detected in type 2 GBM. Additional LOH were more frequently identified in relapses of type 2 GBM than in those showing the type 1 signature. Taken together, our results strongly suggest that recurrences of GBM may display two distinct pattern of accumulation of molecular alterations depending on the profile of the original tumor